Weight-Dependent and -Independent Effects of Semaglutide in Participants With MASH: Secondary Analysis of the Phase 3 ESSENCE Trial

The phase 3 ESSENCE trial is evaluating the efficacy of semaglutide in patients with biopsy-defined MASH and stage 2 or 3 fibrosis.¹ In part 1 of the study, 800 patients were randomly assigned to once weekly semaglutide at 2.4 mg following a 16-week dose escalation (n=534) or to placebo (n=266).¹ The mean age of enrolled patients was 56 years; 57% were female, the mean body weight was 24.5 kg, and 55.9% had T2DM. Semaglutide demonstrated significant improvements in liver-related parameters compared with placebo, including a greater proportion of patients attaining resolution of steatohepatitis without worsening of fibrosis (62.9% vs 34.3%; P<.001) and a greater proportion of patients attaining reductions in liver fibrosis without worsening of steatohepatitis (36.8% vs 22.4%; P<.001). Mean changes in body weight were -10.5% and -2.0%, respectively (P<.001).

Newsome and colleagues presented post-hoc analyses investigating the association between body weight reduction and liver outcomes in the ESSENCE trial.² At week 72, improvements in MASH-related and fibrosis-related endpoints were observed across body weight reduction thresholds. Rates of steatohepatitis resolution without worsening of liver fibrosis among patients receiving semaglutide ranged from 57.1% (43.1% for placebo) in patients with 2% to 5% body weight reduction to 71.5% (56.1% for placebo) in patients with greater than 7% body weight reduction. Rates of improvement in liver fibrosis without worsening of steatohepatitis ranged from 29.3% (22.5% for placebo) in patients with 2% to 5% body weight reduction to 41.8% (37.2% for placebo) in patients with greater than 7% body weight reduction (Figure 4).

Figure 4.

Improvements in metabolic dysfunction-associated steatohepatitis–related histologic and noninvasive test responses were observed across all body weight reduction thresholds in patients treated with semaglutide in the ESSENCE trial.

Adapted from Newsome PN, et al. AASLD abstract 0010. Presented at: The Liver Meeting; November 7-11, 2025; Washington, DC.²

With GLP-1 receptor agonists, some speculate it is loss of weight that leads to improvement, not the agents’ direct effects in the liver. However, in this study, patients with MASH who received semaglutide had improvements in liver health– related parameters, even at low levels of weight reduction. They also had greater improvements on their liver parameters, compared with those who received placebo. This suggests a potential effect of the agent itself not driven solely by weight reduction, although weight loss does improve features of MASLD.

—Nancy S. Reau, MD

Improvements in MASH-related noninvasive test parameters were also observed across body weight reduction thresholds in patients receiving semaglutide, as were improvements in fibrosis-related histologic and noninvasive test responses, including change in ELF scores and VCTE.

The investigators used exploratory mediation analyses to attempt to measure the extent to which the effects of semaglutide on liver parameters were indirect effects (resulting from body weight reduction) or direct effects (not attributed to body weight reduction). They found that MASH-related histologic changes and noninvasive test responses (including histologic resolution of MASH without worsening of liver fibrosis, ALT responses, and FibroScan AST [FAST] responses), as well as fibrosis-related histologic improvement and noninvasive test responses (including improvement in fibrosis without worsening of MASH, VCTE responses, and ELF score responses), were greater in patients receiving semaglutide than in patients receiving placebo, even at a similar amount of weight reduction.

These exploratory findings suggest that factors other than weight reduction may contribute to the liver health benefits observed with semaglutide. However, investigators cautioned that interaction and confounding effects can influence outcomes and may complicate the analysis. They added that a few people on the placebo arm had large amounts of weight loss, which may also complicate the analysis. Moreover, the model requires assumptions that are not always testable. Despite these limitations, the investigators concluded that the benefits of semaglutide on liver health are not driven by weight reduction alone.